Animal models of disease pathophysiology are essential tools in the investigation of complex disorders, both testing etiological hypotheses and serving as a platform for the development of novel therapeutic strategies. However, valid and useful animal models of psychiatric conditions have been difficult to develop, because of the complex nature of their symptomatology and their multitudinous and poorly understood causes. Here we propose a new approach to the development of pathophysiologically grounded models of complex psychiatric disease. Rather than base a model on superficial phenotypic resemblance to the symptoms of a disorder, on response to currently used medications, or on putative causative factors of small effect (such as disease-associated alleles of candidate genes), we propose to base a model on recent post-mortem findings. This approach has significant advantages. First, the effect size of abnormalities seen in postmortem studies is necessarily large, because sample size is necessarily small (in contrast to the real but small effects that can be found in huge genetic studies); basing a model on an abnormality of large effect is more likely to produce disease-relevant downstream consequences. Second, the approach is neutral with respect to etiology; insight into the core features of complex disorders can be generated by modeling core pathophysiological features rather than individual hypothesized causes. Finally, the technical approach we have developed allows flexibility in the timing and extent of the neuronal lesion that underlies the model, and is generalizable to other important neurobiological questions and modeling of other psychiatric conditions. We apply this conceptual approach to the modeling of Tourette syndrome (TS) based on neuropathological findings from the Vaccarino lab, which is collaborating on the current studies. In a pair of recent papers they have documented a reduction of certain key populations of interneurons in the striatum, a structure previously implicated in TS. We will use transgenic and viral reagents to produce an equivalent ablation of these interneurons in mice. These animals will then be tested in behavioral analyses of specific relevance to TS, including prepulse inhibition and striatum-dependent procedural learning; the effect of medications with anti- Tourettic efficacy on observed behavioral abnormalities will be investigated. Finally, since the symptomatology of TS typically waxes and wanes over ontogeny, we will probe the developmental trajectory of the effects of interneuronal ablation by inducing it in young animals and assaying behavior in adolescence and adulthood. These studies serve several important purposes. First, they provide proof of concept for an innovative strategy to modeling the pathphysiology of mental illness. Second, they probe a specific hypothesis of TS, and potentially provide a platform for the development of novel therapeutics. Third, consistent with the goals of the B.R.A.I.N.S. RFA, they provide critical support to an innovative young investigator and his efforts to apply new, sophisiticated methodologies to core problems in the biological study of mental illness. PUBLIC HEALTH RELEVANCE: Animal models of the mechanisms of disease are a critical tool for understanding the mechanisms of complex diseases and for developing new therapies; unfortunately, producing useful models of major psychiatric disorders has proven a daunting challenge, and progress has been slow. Here we describe a new strategy to the development of such models of complex brain disorders, by using molecular tools in mice to reproduce the changes found in post-mortem studies of the brains of patients. This approach is developed in the specific case of Tourette syndrome; but the principal and many of the technical aspects of our approach are generalizable to the modeling and investigation of other neuropsychiatric conditions.